Substituted imidazoles useful in the treatment of inflammatory diseases

ABSTRACT

This invention relates to substituted imidazoles of Formula I 
                         
pharmaceutical compositions containing them, methods of using them and intermediates useful in their manufacture. The compounds of the invention modulate the production of a number of inflammatory cytokines and are useful in the treatment of diseases associated with the overproduction of inflammatory cytokines.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of provisional application Ser. No.60/241,256 filed on Oct. 18, 2000, the complete disclosure of which ishereby incorporated herein by reference for all purposes.

FIELD OF THE INVENTION

This invention relates to a series of substituted imidazoles,pharmaceutical compositions containing them and intermediates used intheir manufacture. The compounds of the invention inhibit the productionof a number of inflammatory cytokines, particularly, TNF-α, and IL-1β.Compounds of this invention are useful in the treatment of diseasesassociated with the overproduction of inflammatory cytokines.

BACKGROUND OF THE INVENTION

The inflammatory cytokines, IL-1β and TNF-α play an important role in anumber of inflammatory diseases such as rheumatoid arthritis. C.Dinarello et al,. Inflammatory cytokines: lnterleukin-1 and TumorNecrosis Factor as Effector Molecules in Autoimmune Diseases Curr. Opin.Immunol. 1991, 3, 941–48. Arthritis is an inflammatory disease whichaffects millions of people and can strike at any joint of the humanbody. Its symptoms range from mild pain and inflammation in affectedjoints, to severe and debilitating pain and inflammation. Although thedisease is associated mainly with aging adults, it is not restricted toadults. The most common arthritis therapy involves the use ofnonsteroidal antiinflammatory drugs (NSAID) to alleviate the symptoms.However, despite their widespread use, many individuals cannot toleratethe doses necessary to treat the disease over a prolonged period oftime. In addition, NSAIDs merely treat the symptoms of disease withoutaffecting the underlying cause. Other drugs, such as methotrexate, goldsalts, D-pencillamine, and prednisone are often used when patients failto respond to NSAIDS. These drugs also have significant toxicities andtheir mechanism of action remain unknown.

Receptor antagonists to IL-1β and monoclonal antibodies to TNF-α havebeen shown to reduce symptoms of rheumatoid arthritis in small-scalehuman clinical trials. In addition to protein based therapies, there aresmall molecule agents which inhibit the production of these cytokinesand have demonstrated activity in animal arthritis models. J. C. Boehmet al., 1-Substituted 4-Aryl-5-pyridinylimidazoles: A New Class ofCytokine Suppressive Drugs With Low 5-Lipoxygenase and CyclooxygenaseInhibitory Potency, J. Med. Chem., 1996, 39, 3929–37. Of these smallmolecule agents, SB 203580 has proved effective in reducing theproduction of TNF-α and IL-1 in LPS stimulated human monocyte cell lineswith IC₅₀ values of 50 to 100 nM. J. Adams et al., Imidazole DerivativesAnd Their Use as Cytokine Inhibitor, International Patent application WO93/14081, Jul. 23, 1993. In addition to this in vitro test, SB 203580inhibits the production of the inflammatory cytokines in rats and miceat IC₅₀ values of 15 to 25 mg/kg. A. M. Badger, et al, PharmacologicalProfile of SB 203580, A Selective Inhibitor of Cytokine SuppressiveBinding Protein/p38 Kinase, in Animal Models of Arthritis, BoneResorption, Endotoxin Shock and Immune Function, The Journal ofPharmacology and Experimental Therapeutics, 1996, 279, 1453–61. Althoughhuman data is currently unavailable for SB 203580, monoclonal antibodiesto TNF-α have proved efficacious in the treatment of rheumatoidarthritis. M. J. Elliot et al., Treatment of Rheumatoid Arthritis withChimeric Monoclonal Antibodies to Tumor Necrosis Factor α, ArthritisRheum. 1993 36, 1681–90. Due to SB 203580's oral activity and potency inanimal models, researchers have suggested that a compound with thisprofile has potential as a viable treatment for rheumatoid arthritis. A.M. Badger, et al. Pharmacological Profile of SB 203580, A SelectiveInhibitor of Cytokine Suppressive Binding Protein/p38 Kinase, in AnimalModels of Arthritis, Bone Resorption, Endotoxin Shock and ImmuneFunction, The Journal of Pharmacology and Experimental Therapeutics,1996, 279, 1453–61.

SB 203580 and other small molecule agents reduce the production ofinflammatory cytokines by inhibiting the activity of a serine/threoninkinase p38 (note other researchers refer to this enzyme as CSBP), at anIC₅₀ of 200 nM. D. Griswold et al., Pharmacology of Cytokine SuppressiveAnti-inflammatory Drug Binding Protein (CSPB), A Novel Stress-inducedKinase, Pharmacology Communications, 1996, 7, 323–29. Although theprecise mechanism of this kinase is unknown, it has been implicated inboth the production of TNF-α and the signaling responses associated withthe TNF-α receptor.

U.S. Pat. No. 5,965,583 (hereby incorporated by reference) describessubstituted imidazoles of the formula:

wherein R₁ is phenyl, substituted phenyl (where the substituents areselected from the group consisting of C₁₋₅alkyl, halogen, nitro,trifluoromethyl and nitrile), or heteroaryl where the heteroarylcontains 5 to 6 ring atoms; R₂ is phenyl, substituted phenyl (where thesubstituents are selected from the group consisting of C₁₋₅alkyl,halogen, nitro, trifluoromethyl and nitrile), heteroaryl where theheteroaryl contains 5 to 6 ring atoms and is optionally C₁₋₅alkylsubstituted; R₃ is hydrogen, SEM, C₁₋₅alkoxycarbonyl, aryloxycarbonyl,arylC₁₋₅alkyloxycarbonyl, arylC₁₋₅alkyl, substituted arylC₁₋₅alkyl(where the aryl substituents are independently selected from one or moremembers of the group consisting of C₁₋₅alkyl, C₁₋₅alkoxy, halogen,amino, C₁₋₅alkylamino, and diC₁₋₅alkylamino), phthalimidoC₁₋₅alkyl,aminoC₁₋₅alkyl, diaminoC₁₋₅alkyl, succinimidoC₁₋₅alkyl,C₁₋₅alkylcarbonyl, arylcarbonyl, C₁₋₅alkylcarbonylC₁₋₅alkyl,aryloxycarbonylC₁₋₅alkyl, heteroarylC₁₋₅alkyl where the heteroarylcontains 5 to 6 ring atoms; R₄ is —A—(CH₂)_(q)—X wherein A is vinylene,ethynylene or

where R₅ is selected from the group consisting of hydrogen, C₁₋₅alkyl,phenyl and phenylC₁₋₅alkyl; q is 0–9; X is selected from the groupconsisting of hydrogen, hydroxy, vinyl, substituted vinyl (where one ormore substituents are selected from the group consisting of fluorine,bromine, chlorine and iodine), ethynyl, substituted ethynyl (where thesubstituents are selected from one or more members of the groupconsisting of fluorine, bromine, chlorine and iodine), C₁₋₅alkyl,substituted C₁₋₅alkyl (where the alkyl substituents are selected fromthe group consisting of one or more C₁₋₅alkoxy, trihaloalkyl,phthalimido and amino), C₃₋₇cycloalkyl, C₁₋₅alkoxy, substitutedC₁₋₅alkoxy (where the alkyl substituents are selected from the groupconsisting of phthalimido and amino), phthalimidooxy, phenoxy,substituted phenoxy (where the phenyl substituents are selected from thegroup consisting of C₁₋₅alkyl, halogen and C₁₋₅alkoxy), phenyl,substituted phenyl (where the phenyl substituents are selected from thegroup consisting of C₁₋₅alkyl, halogen and C₁₋₅alkoxy), arylC₁₋₅alkyl,substituted arylC₁₋₅alkyl (where the aryl substituents are selected fromthe group consisting of C₁₋₅alkyl, halogen and C₁₋₅alkoxy), amino,C₁₋₅alkylamino, diC₁₋₅alkylamino, nitrile, oxime, benzyloxyimino,C₁₋₅alkyloxyimino, phthalimido, succinimido, C₁₋₅alkylcarbonyloxy,phenylcarbonyloxy, substituted phenylcarbonyloxy (where the phenylsubstituents are selected from the group consisting of C₁₋₅alkyl,halogen and C₁₋₅alkoxy), phenylC₁₋₅alkylcarbonyloxy (where the phenylsubstituents are selected from the group consisting of C₁₋₅alkyl,halogen and C₁₋₅alkoxy), aminocarbonyloxy, C₁₋₅alkylaminocarbonyloxy,diC₁₋₅alkylaminocarbonyloxy, C₁₋₅alkoxycarbonyloxy, substitutedC₁₋₅alkoxycarbonyloxy (where the alkyl substituents are selected fromthe group consisting of methyl, ethyl, isopropyl and hexyl),phenoxycarbonyloxy, substituted phenoxycarbonyloxy (where the phenylsubstituents are selected from the group consisting of C₁₋₅alkyl,C₁₋₅alkoxy and halogen), C₁₋₅alkylthio, substituted C₁₋₅alkylthio (wherethe alkyl substituents are selected from the group consisting of hydroxyand phthalimido), C₁₋₅akylsulfonyl, phenylsulfonyl, substitutedphenylsulfonyl (where the phenyl substituents are selected from thegroup consisting of bromine, fluorine, chlorine, C₁₋₅alkoxy andtrifluoromethyl); with the proviso: if A is

q is 0 and X is H, R₃ may not be SEM; and pharmaceutically acceptablesalts thereof as useful in the treatment of diseases associated with theoverproduction of inflammatory cytokines.

U.S. Pat. No. 6,040,320 (hereby incorporated by reference) alsodescribes substituted imidazoles of the formula:

wherein R₁ is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6ring atoms, or substituted phenyl wherein the substituents areindependently selected from one or members of the group consisting ofC₁₋₅alkyl, halogen, nitro, trifluoromethyl and nitrile; R₂ is phenyl,heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms,substituted heteroaryl wherein the substituents are independentlyselected from one or more members of the group consisting of C₁₋₅alkyland halogen, or substituted phenyl wherein the substituents areindependently selected from one or members of the group consisting ofC₁₋₅alkyl, halogen, nitro, trifluoromethyl and nitrile; R₃ is hydrogen,SEM, C₁₋₅alkoxycarbonyl, aryloxycarbonyl, arylC₁₋₅alkyloxycarbonyl,arylC₁₋₅alkyl, phthalimidoC₁₋₅alkyl, aminoC₁₋₅alkyl, diaminoC₁₋₅alkyl,succinimidoC₁₋₅alkyl, C₁₋₅alkylcarbonyl, arylcarbonyl,C₁₋₅alkylcarbonylC₁₋₅alkyl, aryloxycarbonylC₁₋₅alkyl,heteroarylC₁₋₅alkyl where the heteroaryl contains 5 to 6 ring atoms, orsubstituted arylC₁₋₅alkyl wherein the aryl substituents areindependently selected from one or more members of the group consistingof C₁₋₅alkyl, C₁₋₅alkoxy, halogen, amino, C₁₋₅alkylamino, anddiC₁₋₅alkylamino; R₄ is (A)_(n)—(CH₂)_(q)—X wherein A is sulfur orcarbonyl; n is 0 or 1; q is 0–9; X is selected from the group consistingof hydrogen, hydroxy, halogen, vinyl, ethynyl, C₁₋₅alkyl,C₃₋₇cycloalkyl, C₁₋₅alkoxy, phenoxy, phenyl, arylC₁₋₅alkyl, amino,C₁₋₅alkylamino, nitrile, phthalimido, amido, phenylcarbonyl,C₁₋₅alkylaminocarbonyl, phenylaminocarbonyl, arylC₁₋₅alkylaminocarbonyl,C₁₋₅alkylthio, C₁₋₅alkylsulfonyl, phenylsulfonyl, substitutedsulfonamido wherein the sulfonyl substituent is selected from the groupconsisting of C₁₋₅alkyl, phenyl, arylC₁₋₅alkyl, thienyl, furanyl, andnaphthyl; substituted vinyl wherein the substituents are independentlyselected from one or members of the group consisting of fluorine,bromine, chlorine and iodine, substituted ethynyl wherein thesubstituents are independently selected from one or more members of thegroup consisting of fluorine, bromine, chlorine and iodine, substitutedC₁₋₅alkyl wherein the substituents are selected from the groupconsisting of one or more C₁₋₅alkoxy, trihaloalkyl, phthalimido andamino, substituted phenyl wherein the phenyl substituents areindependently selected from one or more members of the group consistingof C₁₋₅alkyl, halogen and C₁₋₅alkoxy, substituted phenoxy wherein thephenyl substituents are independently selected from one or more membersof the group consisting of C₁₋₅alkyl, halogen and C₁₋₅alkoxy,substituted C₁₋₅alkoxy wherein the alkyl substituent is selected fromthe group consisting of phthalimido and amino, substituted arylC₁₋₅alkylwherein the alkyl substituent is hydroxyl, substituted arylC₁₋₅alkylwherein the phenyl substituents are independently selected from one ormore members of the group consisting of C₁₋₅alkyl, halogen andC₁₋₅alkoxy, substituted amido wherein the carbonyl substituent isselected from the group consisting of C₁₋₅alkyl, phenyl, arylC₁₋₅alkyl,thienyl, furanyl, and naphthyl, substituted phenylcarbonyl wherein thephenyl substituents are independently selected from one or members ofthe group consisting of C₁₋₅alkyl, halogen and C₁₋₅alkoxy, substitutedC₁₋₅alkylthio wherein the alkyl substituent is selected from the groupconsisting of hydroxy and phthalimido, substituted C₁₋₅alkylsulfonylwherein the alkyl substituent is selected from the group consisting ofhydroxy and phthalimido, substituted phenylsulfonyl wherein the phenylsubstituents are independently selected from one or members of the groupconsisting of bromine, fluorine, chlorine, C₁₋₅alkoxy andtrifluoromethyl, with the proviso: if A is sulfur and X is other thanhydrogen, C₁₋₅alkylaminocarbonyl, phenylaminocarbonyl,arylC₁₋₅alkylaminocarbonyl, C₁₋₅alkylsulfonyl or phenylsulfonyl, then qmust be equal to or greater than 1; if A is sulfur and q is 1, then Xcannot be C₁₋₂alkyl; if A is carbonyl and q is 0, then X cannot bevinyl, ethynyl, C₁₋₅alkylaminocarbonyl, phenylaminocarbonyl,arylC₁₋₅alkylaminocarbonyl, C₁₋₅alkylsulfonyl or phenylsulfonyl; if A iscarbonyl, q is 0 and X is H, then R₃ is not SEM; if n is 0 and q is 0,then X cannot be hydrogen; and pharmaceutically acceptable salts thereofas useful in the treatment of diseases associated with theoverproduction of inflammatory cytokines.

The object of the present invention is to provide a series ofsubstituted imidazoles, pharmaceutical compositions containing them andintermediates used in their manufacture. Another object is to provide amethod for treating diseases associated with the overproduction ofinflammatory cytokines.

SUMMARY OF THE INVENTION

The invention relates to compounds of Formula I:

wherein:

-   R₁ is selected from the group consisting of phenyl (optionally    substituted with one to five substituents independently selected    from the group consisting of C₁₋₅alkyl, halogen, nitro,    trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl    contains 5 to 6 ring atoms);-   R₂ is selected from the group consisting of phenyl (optionally    substituted with one to five substituents independently selected    from the group consisting of C₁₋₅alkyl, halogen, nitro,    trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl    contains 5 to 6 ring atoms and is optionally substituted with one to    four substituents independently selected from the group consisting    of C₁₋₅alkyl and halogen);-   R₃ is selected from the group consisting of hydrogen, C₁₋₅alkyl,    arylC₁₋₅alkyl (wherein aryl is optionally substituted with one to    four substituents independently selected from the group consisting    of C₁₋₅alkyl, C₁₋₅alkoxy, halogen and amino (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl)), heteroarylC₁₋₅alkyl (wherein heteroaryl    contains 5 to 6 ring atoms), aminoC₁₋₅alkyl, diaminoC₁₋₅alkyl,    phthalimidoC₁₋₅alkyl, succinimidoC₁₅alkyl, SEM, C₁₋₅alkylcarbonyl,    C₁₋₅alkylcarbonylC₁₋₅alkyl, C₁₋₅alkoxycarbonyl, arylcarbonyl,    aryloxycarbonyl, arylC₁₋₅alkyloxycarbonyl and    aryloxycarbonylC₁₋₅alkyl;-   A is a five to seven member heterocyclyl ring optionally substituted    with one to two substituents independently selected from X; wherein    the ring has an unsaturated bond of attachment at a ring carbon    atom; has a ring nitrogen atom substituted with a substituent    selected from W adjacent to the ring carbon of attachment; has a    ring carbon atom adjacent to the ring carbon of attachment;    optionally has 1 or 2 double bonds formed in the ring between    adjacent ring members; and, optionally has 1 or 2 ring members    independently selected from the group consisting of O, N and S;-   W is a substituent selected from the group consisting of hydrogen,    C₁₋₅alkyl, C₁₋₅alkoxy, aminoC₁₋₅alkyl (wherein amino is optionally    substituted with one to two substituents independently selected from    C₁₋₅alkyl), arylC₁₋₅alkyl and heteroarylC₁₋₅alkyl (wherein the aryl,    heteroaryl and C₁₋₅alkyl portions of any of the foregoing    substituents are optionally substituted with one to three    substituents independently selected from the group consisting of    halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl, heteroaryl, amino (wherein    amino is optionally substituted with one to two substituents    independently selected from C₁₋₅alkyl) and nitrile); and,-   X is a substituent selected from the group consisting of C₁₋₅alkyl,    C₁₋₅alkenyl, C₁₋₅alkynyl, C₁₋₅alkoxy, amino (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl), aminoC₁₋₅alkyl (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl), aryl, arylC₁₋₅alkyl, heteroaryl and    heteroarylC₁₋₅alkyl (wherein the aryl, heteroaryl and C₁₋₅alkyl    portions of any of the foregoing substituents are optionally    substituted with one to two substituents independently selected from    the group consisting of halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl,    heteroaryl, amino (wherein amino is optionally substituted with one    to two substituents independently selected from C₁₋₅alkyl) and    nitrile);    and pharmaceutically acceptable salts thereof.

The present invention includes a method for preparing a compound ofFormula I:

wherein

-   R₁ is selected from the group consisting of phenyl (optionally    substituted with one to five substituents independently selected    from the group consisting of C₁₋₅alkyl, halogen, nitro,    trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl    contains 5 to 6 ring atoms);-   R₂ is selected from the group consisting of phenyl (optionally    substituted with one to five substituents independently selected    from the group consisting of C₁₋₅alkyl, halogen, nitro,    trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl    contains 5 to 6 ring atoms and is optionally substituted with one to    four substituents independently selected from the group consisting    of C₁₋₅alkyl and halogen);-   R₃ is selected from the group consisting of hydrogen, C₁₋₅alkyl,    arylC₁₋₅alkyl (wherein aryl is optionally substituted with one to    four substituents independently selected from the group consisting    of C₁₋₅alkyl, C₁₋₅alkoxy, halogen and amino (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl)), heteroarylC₁₋₅alkyl (wherein heteroaryl    contains 5 to 6 ring atoms), aminoC₁₋₅alkyl, diaminoC₁₋₅alkyl,    phthalimidoC₁₋₅alkyl, succinimidoC₁₋₅alkyl, SEM, C₁₋₅alkylcarbonyl,    C₁₋₅alkylcarbonylC₁₋₅alkyl, C₁₋₅alkoxycarbonyl, arylcarbonyl,    aryloxycarbonyl, arylC₁₋₅alkyloxycarbonyl and    aryloxycarbonylC₁₋₅alkyl;-   A is a five to seven member heterocyclyl ring optionally substituted    with one to two substituents independently selected from X; wherein    the ring has an unsaturated bond of attachment at a ring carbon    atom; has a ring nitrogen atom substituted with a substituent    selected from W adjacent to the ring carbon of attachment; has a    ring carbon atom adjacent to the ring carbon of attachment;    optionally has 1 or 2 double bonds formed in the ring between    adjacent ring members; and, optionally has 1 or 2 ring members    independently selected from the group consisting of O, N and S;-   W is a substituent selected from the group consisting of hydrogen,    C₁₋₅alkyl, C₁₋₅alkoxy, aminoC₁₋₅alkyl (wherein amino is optionally    substituted with one to two substituents independently selected from    C₁₋₅alkyl), arylC₁₋₅alkyl and heteroarylC₁₋₅alkyl (wherein the aryl,    heteroaryl and C₁₋₅alkyl portions of any of the foregoing    substituents are optionally substituted with one to three    substituents independently selected from the group consisting of    halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl, heteroaryl, amino (wherein    amino is optionally substituted with one to two substituents    independently selected from C₁₋₅alkyl) and nitrile); and,-   X is a substituent selected from the group consisting of C₁₋₅alkyl,    C₁₋₅alkenyl, C₁₋₅alkynyl, C₁₋₅alkoxy, amino (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl), aminoC₁₋₅alkyl (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl), aryl, arylC₁₋₅aIkyl, heteroaryl and    heteroarylC₁₋₅alkyl (wherein the aryl, heteroaryl and C₁₋₅alkyl    portions of any of the foregoing substituents are optionally    substituted with one to two substituents independently selected from    the group consisting of halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl,    heteroaryl, amino (wherein amino is optionally substituted with one    to two substituents independently selected from C₁₋₅alkyl) and    nitrile);    and pharmaceutically acceptable salts thereof; comprising,-   converting an intermediate compound of Formula II

wherein

-   Y is a three to five member linear alkylene, alkenylene,    heteroalkylene or heteroalkenylene chain optionally substituted with    one to two substituents independently selected from X; wherein the    alkenylene and heteroalkenylene chain has 1 or 2 double bonds formed    in the chain between adjacent members; and, wherein the    heteroalkylene and heteroalkenylene chain has 1 or 2 members    independently selected from the group consisting of O, N and S; and,-   all other substituents are as previously defined;-   by ammonolysis, using an excess of a compound selected from H₂N(W)    in an appropriate solvent, to form a secondary amine intermediate of    Formula III; and,

-   coupling the amine at the 2 position of the triple bond by a Michael    addition, in the presence of appropriate reagents and solvents, to    form the compound of Formula I.

The present invention also includes an intermediate compound of FormulaII:

wherein

-   R₁ is selected from the group consisting of phenyl (optionally    substituted with one to five substituents independently selected    from the group consisting of C₁₋₅alkyl, halogen, nitro,    trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl    contains 5 to 6 ring atoms);-   R₂ is selected from the group consisting of phenyl (optionally    substituted with one to five substituents independently selected    from the group consisting of C₁₋₅alkyl, halogen, nitro,    trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl    contains 5 to 6 ring atoms and is optionally substituted with one to    four substituents independently selected from the group consisting    of C₁₋₅alkyl and halogen);-   R₃ is selected from the group consisting of hydrogen, C₁₋₅alkyl,    arylC₁₋₅alkyl (wherein aryl is optionally substituted with one to    four substituents independently selected from the group consisting    of C₁₋₅alkyl, C₁₋₅alkoxy, halogen and amino (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl)), heteroarylC₁₋₅alkyl (wherein heteroaryl    contains 5 to 6 ring atoms), aminoC₁₋₅alkyl, diaminoC₁₋₅alkyl,    phthalimidoC₁₋₅alkyl, succinimidoC₁₋₅alkyl, SEM, C₁₋₅alkylcarbonyl,    C₁₋₅alkylcarbonylC₁₋₅alkyl, C₁₋₅alkoxycarbonyl, arylcarbonyl,    aryloxycarbonyl, arylC₁₋₅alkyloxycarbonyl and    aryloxycarbonylC₁₋₅alkyl; and,-   Y is a three to five member linear alkylene, alkenylene,    heteroalkylene or heteroalkenylene chain optionally substituted with    one to two substituents independently selected from X; wherein the    alkenylene and heteroalkenylene chain has 1 or 2 double bonds formed    in the chain between adjacent members; and, wherein the    heteroalkylene and heteroalkenylene chain has 1 or 2 members    independently selected from the group consisting of O, N and S;-   with the proviso that Y cannot be selected from (CH₂)₃;    and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are useful as inhibitors of TNF-αand IL-1. Some of the instant compounds are more active than others and,thereby, have a structure activity relationship that may be preferred,more preferred or most preferred.

Compounds of Formula I that are preferred include a compound wherein:

-   R₁ is phenyl (optionally substituted with one to five substituents    independently selected from the group consisting of C₁₋₅alkyl and    halogen);-   more preferably, R₁ is phenyl substituted with a substituent    selected from halogen;-   and, most preferably, R₁ is phenyl substituted with fluorine.

Other compounds of Formula I that are preferred include a compoundwherein:

-   R₂ is heteroaryl (wherein heteroaryl contains 5 to 6 ring atoms and    is optionally substituted with one to four substituents    independently selected from the group consisting of C₁₋₅alkyl and    halogen);-   more preferably, R₂ is selected from the group consisting of    2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl,    2-pyrrolinyl, 3-pyrrolinyl, 4-pyrrolinyl, 5-pyrrolinyl, 2-oxazolyl,    4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,    2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-imidazolinyl,    4-imidazolinyl, 5-imidazolinyl, 3-pyrazolyl, 4-pyrazolyl,    5-pyrazolyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,    3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl,    4-isothiazolyl, 5-isothiazolyl, 4-1,2,3-oxadiazolyl,    5-1,2,3-oxadiazolyl, 4-1,2,3-triazolyl, 5-1,2,3-triazolyl,    2-1,3,4-thiadiazolyl, 5-1,3,4-thiadiazolyl, 2-pyridinyl,    3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl,    2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,    3-pyrazinyl and 2-1,3,5-triazinyl optionally substituted with one    substituent selected from C₁₋₅alkyl; and,-   most preferably, R₂ is selected from the group consisting of    4-pyridinyl, 4-pyrimidinyl and (2-butyl)pyridin-4-yl.

Embodiments of compounds of Formula I that are preferred also include acompound wherein:

-   R₃ is selected from the group consisting of hydrogen, C₁₋₅alkyl and    arylC₁₋₅alkyl (wherein aryl is optionally substituted with one to    four substituents independently selected from the group consisting    of C₁₋₅alkyl, C₁₋₅alkoxy, halogen and amino (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl));-   more preferably, R₃ is selected from the group consisting of    hydrogen and phenylC₁₋₅alkyl (wherein phenyl is optionally    substituted with one substituent selected from C₁₋₅alkoxy); and,-   most preferably, R₃ is selected from the group consisting of benzyl,    phenethyl and phenylpropyl.

Other preferred embodiments of compounds of Formula I include a compoundwherein:

-   A is selected from the group consisting of pyrrolidinyl,    imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl,    thiomorpholinyl, piperazinyl, hexahydro-1H-azepine,    hexahydro-1H-1,3-diazepine, hexahydro-1,3-oxazepine,    hexahydro-1,3-thiazepine and hexahydro-1H-1,3,5-triazepine; and,-   more preferably, A is selected from the group consisting of    pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl and    piperazinyl.

Additional compounds of Formula I that are preferred include a compoundwherein:

-   W is a substituent selected from the group consisting of hydrogen,    C₁₋₅alkyl and C₁₋₅alkoxy (wherein C₁₋₅alkyl for any of the foregoing    substituents is optionally substituted with one to three    substituents independently selected from the group consisting of    halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl, heteroaryl, amino (wherein    amino is optionally substituted with one to two substituents    independently selected from C₁₋₅alkyl) and nitrile);-   more preferably, W is a substituent selected from the group    consisting of hydrogen and C₁₋₅alkyl; and,-   most preferably, W is a substituent selected from the group    consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl    and t-butyl.

Preferred embodiments of compounds of Formula I also include a compoundwherein:

-   X is a substituent selected from the group consisting of C₁₋₅alkyl,    C₁₋₅alkenyl, C₁₋₅alkynyl, C₁₋₅alkoxy and amino (wherein amino is    optionally substituted with one to two substituents independently    selected from C₁₋₅alkyl);-   more preferably, X is a substituent selected from C₁₋₅alkyl; and,-   most preferably, X is a substituent selected from the group    consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl and    t-butyl.

The preferred compounds of Formula I include a compound of formula:

and pharmaceutically acceptable salts thereof.

In a preferred embodiment of the method of the present invention, Y is athree to five member linear alkylene chain optionally substituted withone to two substituents independently selected from X. In a morepreferred embodiment of the instant method, Y is an unsubstituted threeto five member linear alkylene chain.

In a preferred embodiment of the intermediate compound of Formula II, Yis a four to five member linear alkylene chain optionally substitutedwith one to two substituents independently selected from X. In a morepreferred embodiment of the instant compound, Y is an unsubstituted fourto five member linear alkylene chain.

The terms used in describing the invention are commonly used and knownto those skilled in the art. However, the terms that could have othermeanings are defined. The term “independently” means that when there aremore than one substituent, the substituents may be different.

The term “alkyl” refers to straight and branched-chain alkyl groups;“alkoxy” refers O-alkyl where alkyl is as defined supra. The termcycloalkyl refers to a cyclic alkyl ring of five to seven carbon atommembers. Examples of such cyclic alkyl rings include pentyl, hexyl orheptyl.

In the present invention, the term heterocyclyl refers to the “A”substituent which comprises a cyclic alkyl ring of five to seven memberswherein at least one member is a first nitrogen atom substituted with asubstituent selected from W.

The heterocyclyl ring may contain up to two heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur. Up totwo carbon atom ring members may be optionally substituted with one totwo substituents selected from X or may have empty valences satisfied bythe ring itself. Nitrogen atom ring members in addition to the firstnitrogen atom ring member may be substituted with one substituentselected from W or may have empty valences satisfied by the ring itself.

In the compounds of the present invention, the “A” substituentheterocyclyl ring is attached to the 2 position of the imidazolescaffold via a ring carbon atom and a linking carbon atom. The ringcarbon atom forms a double bond with the linking carbon atom. Theheterocyclyl ring contains at least a single nitrogen heteroatomsubstituted with a substituent selected from W. The single nitrogen atomwill be adjacent to the ring carbon atom of attachment. The ring carbonof attachment will also have an adjacent ring carbon.

For instant compounds of the invention, the carbon atom ring membersthat form the heterocyclyl ring “A” substituent are fully saturatedexcept for the single carbon of attachment. Other compounds of theinvention may have a partially unsaturated heterocyclyl ring that formsthe “A” substituent. Preferred partially unsaturated heterocyclyl ringsmay contain one or two double bonds. Such compounds are not consideredto be fully aromatic and are not referred to as heteroaryl compounds.Therefore, a five member heterocyclyl ring that forms the “A”substituent may optionally have a double bond formed in the ring betweenadjacent ring members; a six or seven member heterocyclyl ring thatforms the “A” substituent may have two double bonds formed in the ringbetween adjacent ring members. The carbon ring member of attachment maystably form only a single bond with an adjacent carbon ring member andthe first nitrogen ring member. The first nitrogen ring membersubstituted with a substituent selected from W links the carbon ringmember of attachment to another ring member (which may be a carbon or asecond nitrogen atom) and may stably form only a single bond with bothring members.

The term “alkylene” refers to a straight chain alkyl linking group. Theterm “alkylene” refers to a straight chain alkenyl linking group whereinone or two double bonds are formed in the chain between adjacentmembers. The term “heteroalkylene” refers to a straight chain alkyllinking group wherein at least one member is a heteroatom independentlyselected from the group consisting of nitrogen, oxygen and sulfur. Theheteroalkylene chain may contain up to two heteroatoms. Similarly, theterm “heteroalkenylene” refers to a straight chain alkenyl linking groupwherein one or two double bonds are formed in the chain between adjacentchain members.

In particular, the “Y” substituent comprises a three to five memberalkylene, alkenylene, heteroalkylene or heteroalkenylene chainoptionally substituted with one to two substituents independentlyselected from X. Up to two carbon atom chain members may be optionallysubstituted with one to two substituents selected from X or may haveempty valences satisfied by the ring itself. A nitrogen heteroatom chainmember may be optionally substituted with one substituent selected fromW or may have empty valences satisfied by the ring itself.

In the compounds of the present invention, the “Y” substituent isattached to an adjacent unsaturated carbon atom. The terminal atom ofthe “Y” substituent attached to the adjacent carbon atom is either acarbon atom or a heteroatom that forms a stable chemical bond within the“A” substituent heterocyclyl ring. The adjacent carbon atom forms atriple bond with a linking carbon atom whereby the “Y” substituent isattached to the 2 position of the imidazole scaffold. For instantcompounds of the invention, the “Y” substituent is a fully saturatedalkylene or heteroalkylene chain. Other compounds of the invention mayhave a partially unsaturated alkenylene or heteroalkenylene chain thatforms the “Y” substituent. Preferred unsaturated chains may contain oneor two double bonds.

The term aryl refers to a single aromatic ring of six carbon members ora bicyclic aromatic ring of ten carbon members. Examples of such arylrings include phenyl and naphthyl.

The term heteroaryl refers to an aromatic ring of five or six memberswherein the ring has at least one heteroatom member. Suitableheteroatoms include nitrogen, oxygen or sulfur. In the case offive-membered rings, the heteroaryl ring contains one member ofnitrogen, oxygen or sulfur and, in addition, may contain up to twoadditional nitrogens. In the case of six-membered rings, the heteroarylring may contain from one to three nitrogen atoms. For the case whereinthe six member ring has three nitrogens, at most two nitrogen atoms areadjacent.

In the present invention, the term “Michael addition” refers to thenucleophilic addition of a carbanion (such as the nitrogen portion of—N(H)(W) in a compound of Formula IV) to the β position of anα,β-unsaturated carbon-carbon bond (such as the 2 position of the triplebond portion of a compound of Formula IV), a process known to thoseskilled in the art.

As used in this invention the term “cytokine” refers to the proteinsTNF-α and IL-1β. Cytokine related disorders are diseases of humans andother mammals where the overproduction of cytokines causes the symptomsof the disease. The overproduction of the cytokines, TNF-α and IL-1β hasbeen linked to a number of diseases including, but not limited to,rheumatoid arthritis, inflammatory bowel disease, septic shockosteoporosis, osteoarthritis, neuropathic pain, HIV replication, HIVdementia, viral myocarditis, insulin-dependent diabetes, non-insulindependent diabetes, periodontal disease, restenosis, alopecia areta,T-cell depletion in HIV infection or AIDS, psoriasis, acutepancreatitis, allograft rejection, allergic inflammation in the lung,atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease,stroke, Crohn's disease, inflammatory bowel disease, ischemia,congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma,Guillain-Barre Syndrome, and systemic lupus erythematosus.

The term “effective dose” refers to an amount of a compound of Formula Iwhich reduces the amount of TNFα and/or IL-1β which may be detected in amammal suffering from a cytokine mediated disorder. In addition, theterm “effective dose” refers to an amount of a compound of Formula Iwhich reduces the symptoms of a cytokine related disorder.

The term “FCS” represents fetal calf serum, “TCA” representstrichloroacetic acid and the “RPMI” represents the medium from theRoswell Park Memoria Inst. (Sigma cat #R0833). “SEM” refers to2-(trimethylsilyl)ethoxymethyl) and “LDA” refers to lithiumdiisopropylamide. The symbol “Ph” refers to phenyl and “PHT” refers tophthalimido.

The compounds of the present invention may be prepared by the followingscheme, which may produce more than one embodiment of the instantcompounds. Such embodiments are intended to be included within the scopeof this invention. U.S. Pat. No. 5,965,583 (heretofore incorporated byreference) and U.S. Pat. No. 6,040,320 (heretofore incorporated byreference) disclose schemes and procedures which may be used to prepareintermediates for use in the present invention. Compounds prepared fromsuch intermediates are intended to be within the scope of thisinvention.

The compounds of the invention may be prepared as shown in Scheme A.Compound A1 to the Compound of Formula II depicted in Scheme A wereproduced according to the procedure described for Example 14 in U.S.Pat. No. 5,965,583. Other imidazoles, which may be prepared using themethods of the present invention, unsubstituted at the 1-position aresubject to tautomerization; therefore, substituents for R₁ and R₂ may beinterchangeable when R₃ is hydrogen.

Intermediate Compound A1 was synthesized according to the methodology ofLantos et. al. J. Org. Chem. 1988, 53, 4223–4227. Compound A1 wasreacted with selenium dioxide (SeO₂) in dioxane at about 80° C. andafforded diketone Compound A2. Treatment of Compound A2 withphenylpropylamine, ammonium acetate and formaldehyde or a formaldehydeequivalent such as hexamethylenetetraamine in acetic acid at about80–100° C. yielded imidazole Compound A3. The imidazole Compound A3 wasiodinated by deprotonation at the number 2 carbon with a strong basesuch as lithium diisopropylamide (LDA) at about −20 to about −78° C.followed by addition of iodine to give the iodinated imidazole CompoundA4. Compound A4 was then coupled with a compound of the formula—CC(Y)Cl; wherein Y is as defined herein, using a palladium (II)[Pd(II)] catalyst such as tetrakis tris(triphenylphosphine) palladium(II) in acetonitrile and excess triethylamine at 80° C. for 3–18 hoursto obtain the intermediate Compound of Formula II. The Compound ofFormula II was reacted with excess alkylamine H₂N(W) in methanol atabout 70° C. to about 80° C. for about 3 to about 18 hours (h) andresulted in a secondary amine intermediate which was then subjected toan intramolecular Michael addition to obtain the target Compound ofFormula I.

Compounds of Formula I may be used in pharmaceutical compositions totreat patients (humans and other primates) with disorders related to theoverproduction of inflammatory cytokines, particularly TNF-α. Thepreferred route is oral administration, however compounds may beadministered by intravenous infusion or topical administration. Oraldoses range from about 0.01 to 100 mg/kg, daily. Some compounds of theinvention may be orally dosed in the range of about 0.01 to about 50mg/kg daily, while others may be dosed at 0.01 to about 20 mg/kg daily.Infusion doses can range from about 1.0 to 1.0×10⁴ μg/kg/min ofinhibitor, admixed with a pharmaceutical carrier over a period rangingfrom several minutes to several days. For topical administrationcompounds of Formula I may be mixed with a pharmaceutical carrier at aconcentration of about 0.1 % to about 10% of drug to vehicle.

The novel compounds of Formula I and pharmaceutical compositions thereofof this invention inhibit the in vitro activity of p-38 in the nanomolarrange. In addition, the compounds and pharmaceutical compositionsthereof inhibit the in vitro secretion of TNF-α and IL-1β in thenanomolar range. Animal models demonstrate the inhibition of LPS inducedTNF-α, as well as the inhibition of rheumatoid arthritis.

With this range of activity, the compounds and associated pharmaceuticalcompositions of the invention are useful in the treatment of a varietyof cytokine related disorders including, but no limited to, rheumatoidarthritis, inflammatory bowel disease, septic shock osteoporosis,osteoarthritis, neuropathic pain, HIV replication, HIV dementia, viralmyocarditis, insulin-dependent diabetes, non-insulin dependent diabetes,periodontal disease, restenosis, alopecia areta, T-cell depletion in HIVinfection or AIDS, psoriasis, acute pancreatitis, allograft rejection,allergic inflammation in the lung, atherosclerosis, multiple sclerosis,cachexia, Alzheimer's disease, stroke, Crohn's disease, inflammatorybowel disease, ischemia, congestive heart failure, pulmonary fibrosis,hepatitis, glioblastoma, Guillain-Barre Syndrome, and systemic lupuserythematosus.

Pharmaceutical compositions of the present invention can be preparedusing conventional pharmaceutical excipients and compounding techniques.Oral dosage forms may be elixirs, syrups, capsules tablets and the like.Where the typical solid carrier is an inert substance such as lactose,starch, glucose, methyl cellulose, magnesium stearate, dicalciumphosphate, mannitol and the like; and typical liquid oral excipientsinclude ethanol, glycerol, water and the like. All excipients may bemixed as needed with disintegrants, diluents, granulating agents,lubricants, binders and the like using conventional techniques known tothose skilled in the art of preparing dosage forms. Parenteral dosageforms may be prepared using water or another sterile carrier.

Typically the compounds of Formula I are isolated and used as freebases, however the compounds may be isolated and used as theirpharmaceutically acceptable salts. Examples of such salts includehydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic,fumaric, malic, tartatic, citric, benzoic, mandelic, methanesulfonic,hydroethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic andsaccharic.

In order to illustrate the invention the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which arereadily apparent to them. However those methods are deemed to be withinthe scope of this invention.

SYNTHETIC EXAMPLES Example 1

4-[4-(4-fluorophenyl)-2-[(E)-(1-methyl-2-pyrrolidinylidene)methyl]-1-(3-phenylpropyl)-1H-imidazol-5-yl]-pyridine(Compound 1)

The starting material for Compound 1 was prepared as illustrated by theprocedure used for Compound 14, found in U.S. Pat. No. 5,965,583.Compound 14 (1.39 grams, 3.04 mmol) was placed in a tube and a 2Nsolution of methylamine (15 mL) and 4-dimethylaminopyridine (5 mol%) wasadded. The tube was sealed and placed in an oil bath heated to about 70°C. for about 24 h. The tube was removed from the oil bath and allowed tocool to ambient temperature before being opened. The mixture wasevaporated in vacuo and the crude product was purified by columnchromatography (silica gel) using a mobile phase consisting of methylenechloride:methanol in a 19:1 (v/v) ratio and afforded Compound 1 whichwas recrystallized from ethyl acetate-hexane; m.p. 171–172° C.; MS 453(MH⁺). ¹H NMR (CDCl₃) δ 8.59 (d, 2H) 4.52 (s, 1H, exch.), 2.75 (s, 3H,CH₃).

Example 24-[4-(4-fluorophenyl)-2-[(E)-(1-ethyl-2-pyrrolidinylidene)methyl]-1-(3-phenylpropyl)-1H-imidazol-5-yl]-pyridine(Compound 2)

Following the procedure of Example 1 and substituting the appropriatestarting materials, compounds and reagents, Compound 2 was alsoprepared; m.p. 126.6–127.6° C.; MS 467 (MH⁺).

BIOLOGICAL EXAMPLES

As discussed previously, agents which inhibit the activity of the enzymep38, inhibit the production of the inflammatory cytokines TNF-α andIL-1. The biological activity of the compounds of the present inventionwas demonstrated by in vitro and in vivo assays.

Example 3

Compounds of the invention were measured for their ability to inhibitthe activity of p38 in an in vitro whole cell assay using peripheralblood mononuclear cells (“PBMC” ) obtained from human blood as follows.Freshly obtained venous blood was anticoagulated with heparin, dilutedwith an equal volume of phosphate buffered saline (“PBS” ) and placed ina sterile tube or other container. Aliquots (30 mL) of this mixture weretransferred to centrifuge tubes which were underlaid with Ficoll-Hypaque(15 mL). The prepared tubes were centrifuged at 400×g without brakingfor 30 min at room temperature. Approximately ½ to ⅔ of the plateletlayer above the mononuclear cell band was removed with a pipet. Themajority of the mononuclear cell layer was carefully removed using apipet and these PBMCs were diluted with PBS and spun at 600×g for 15min. The resulting PBMCs were washed with another portion of PBS andspun at 400×g for 10 min at room temperature. The recovered pellets werediluted in low endotoxin RPMI/1% FCS culture medium and gave a cellconcentration of 0.5–2.0×10⁶ PMBC/mL. A small volume of the suspensionwas removed for counting on a hemocytometer and the remainingpreparation was centrifuged at 200×g for 15 min at room temperature. Therecovered pelleted PMBC were resuspended in RPMI/1% FCS to aconcentration of 1.67×10⁶/mL.

To run the assay, the PBMC suspension (180 μL) was transferred toduplicate wells of a 96-well flat-bottom microtiter plate and incubatedfor 1 h at 37° C. A solution of test compound (10 μL: prepared at 20×the desired final concentration) was added to each well and the platewas incubated for 1 h at 37° C. A solution (10 μL) of LPS in RPMI/1% FCS(200 ng/mL) was added and the wells were incubated overnight at 37° C.The supernate (100 μL) was removed from each well and diluted withRPMI/1% FCS (400 μL). The samples were analyzed for TNF-α using acommercial ELISA kit (Genzyme), resulting in data as shown in Table A.

Example 4

The ability of the compounds of Formula I to inhibit LPS induced TNF-αproduction was demonstrated in the following in vivo rodent assay. Mice(BALB/cJ females, Jackson Laboratories) or rats (Lewis males, CharlesRiver) were fasted for 30 min prior to oral dosing with 5–10 mL/kg oftest compound at 5–50 mg/kg. Thirty minutes after dosing, the animalswere injected intraperitoneally with LPS at 1 mg/kg and returned totheir cages for 1 h. Animals were anesthetized by CO₂, exsanguinated bycardiac puncture and whole blood collected (0.1–0.7 mL). The blood wasallowed to clot and serum was transferred to a centrifuge tube. Thissample was centrifuged, serum was collected, aliquoted and frozen at −80C. Samples were tested by commercial ELISAs for TNF-α (Endogen for mouseTNF-α and Biosource for rat TNF-α), resulting in data as shown in TableA.

TABLE A

TNF-α % Inhibition Mouse TNF-α Cpd W IC₅₀ (nM) 25 mg/kg 10 mg/kg 1methyl 15 99 77 2 ethyl 17 98 89

1. A compound of Formula I

wherein: R₁ is selected from the group consisting of phenyl (optionally substituted with one to five substituents independently selected from the group consisting of C₁₋₅alkyl, halogen, nitro, trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl contains 5 to 6 ring atoms); R₂ is selected from the group consisting of phenyl (optionally substituted with one to five substituents independently selected from the group consisting of C₁₋₅alkyl, halogen, nitro, trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl contains 5 to 6 ring atoms and is optionally substituted with one to four substituents independently selected from the group consisting of C₁₋₅alkyl and halogen); R₃ is selected from the group consisting of hydrogen, C₁₋₅alkyl, arylC₁₋₅alkyl (wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C₁₋₅alkyl, C₁₋₅alkoxy, halogen and amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl)), heteroarylC₁₋₅alkyl (wherein heteroaryl contains 5 to 6 ring atoms), aminoC₁₋₅alkyl, diaminoC₁₋₅alkyl, phthalimidoC₁₋₅alkyl, succinimidoC₁₋₅alkyl, SEM, C₁₋₅alkylcarbonyl, C₁₋₅alkylcarbonylC₁₋₅alkyl, C₁₋₅alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, arylC₁₋₅alkyloxycarbonyl and aryfoxycarbonylC₁₋₅alkyl; A is a five to seven member heterocyclyl ring optionally substituted with one to two substituents independently selected from X; wherein the ring has an unsaturated bond of attachment at a ring carbon atom; has a ring nitrogen atom substituted with a substituent selected from W adjacent to the ring carbon of attachment; has a ring carbon atom adjacent to the ring carbon of attachment; optionally has 1 or 2 double bonds formed in the ring between adjacent ring members; and, optionally has 1 or 2 ring members independently selected from the group consisting of O, N and S; W is a substituent selected from the group consisting of hydrogen, C₁₋₅alkyl, C₁₋₅alkoxy, aminoC₁₋₅alkyl (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl), arylC₁₋₅alkyl and heteroarylC₁₋₅alkyl (wherein the aryl, heteroaryl and C₁₋₅alkyl portions of any of the foregoing substituents are optionally substituted with one to three substituents independently selected from the group consisting of halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl, heteroaryl, amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl) and nitrile); and, X is a substituent selected from the group consisting of C₁₋₅alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl,  C₁₋₅alkoxy, amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl), aminoC₁₋₅alkyl (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl), aryl, arylC₁₋₅alkyl, heteroaryl and heteroarylC₁₋₅alkyl (wherein the aryl, heteroaryl and C₁₋₅alkyl portions of any of the foregoing substituents are optionally substituted with one to two substituents independently selected from the group consisting of halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl, heteroaryl, amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl) and nitrile); and pharmaceutically acceptable salts thereof.
 2. A compound of claim 1 wherein R₁ is phenyl (optionally substituted with one to five substituents independently selected from the group consisting of C₁₋₅alkyl and halogen).
 3. A compound of claim 2 wherein R₁ is phenyl substituted with a substituent selected from halogen.
 4. A compound of claim 3 wherein R₁ is phenyl substituted with fluorine.
 5. A compound of claim 1 wherein R₂ is heteroaryl (wherein heteroaryl contains 5 to 6 ring atoms and is optionally substituted with one to four substituents independently selected from the group consisting of C₁₋₅alkyl and halogen).
 6. A compound of claim 5 wherein R₂ is selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 4-1,2,3-oxadiazolyl, 5-1,2,3-oxadiazolyl, 4-1,2,3-triazolyl, 5-1,2,3-triazolyl, 2-1,3,4-thiadiazolyl, 5-1,3,4-thiadiazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl and 2-1,3,5-triazinyl optionally substituted with one substituent selected from C₁₋₅alkyl.
 7. A compound of claim 6 wherein R₂ is selected from the group consisting of 4-pyridinyl, 4-pyrimidinyl and (2-butyl)pyridin-4-yl.
 8. A compound of claim 1 wherein R₃ is selected from the group consisting of hydrogen, C₁₋₅alkyl and arylC₁₋₅alkyl (wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C₁₋₅alkyl, C₁₋₅alkoxy, halogen and amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl)).
 9. A compound of claim 8 wherein R₃ is selected from the group consisting of hydrogen and phenylC₁₋₅alkyl (wherein phenyl is optionally substituted with one substituent selected from C₁₋₅alkoxy).
 10. A compound of claim 9 wherein R₃ is selected from the group consisting of benzyl, phenethyl and phenylpropyl.
 11. A compound of claim 1 wherein A is selected from the group consisting of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, hexahydro-1H-azepine, hexahydro-1H-1,3-diazepine, hexahydro-1,3-oxazepine, hexahydro-1,3-thiazepine and hexahydro-1H-1,3,5-triazepine.
 12. A compound of claim 11 wherein A is selected from the group consisting of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl and piperazinyl.
 13. A compound of claim 1 wherein W is a substituent selected from the group consisting of hydrogen, C₁₋₅alkyl and C₁₋₅alkoxy (wherein C₁₋₅alkyl for any of the foregoing substituents is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl, heteroaryl, amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl) and nitrile).
 14. A compound of claim 13 wherein W is a substituent selected from the group consisting of hydrogen and C₁₋₅alkyl.
 15. A compound of claim 14 wherein W is a substituent selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
 16. A compound of claim 1 wherein X is a substituent selected from the group consisting of C₁₋₅alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl, C₁₋₅alkoxy and amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl).
 17. A compound of claim 16 wherein X is a substituent selected from C₁₋₅alkyl.
 18. A compound of claim 17 wherein X is a substituent selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
 19. A compound of claim 1 selected from

and pharmaceutically acceptable salts thereof.
 20. A compound of claim 1 selected from

and pharmaceutically acceptable salts thereof.
 21. A method for preparing a compound of Formula I

wherein R₁ is selected from the group consisting of phenyl (optionally substituted with one to five substituents independently selected from the group consisting of C₁₋₅alkyl, halogen, nitro, trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl contains 5 to 6 ring atoms); R₂ is selected from the group consisting of phenyl (optionally substituted with one to five substituents independently selected from the group consisting of C₁₋₅alkyl, halogen, nitro, trifluoromethyl and nitrile) and heteroaryl (wherein heteroaryl contains 5 to 6 ring atoms and is optionally substituted with one to four substituents independently selected from the group consisting of C₁₋₅alkyl and halogen); R₃ is selected from the group consisting of hydrogen, C₁₋₅alkyl, arylC₁₋₅alkyl (wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C₁₋₅alkyl, C₁₋₅alkoxy, halogen and amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl)), heteroarylC₁₋₅alkyl (wherein heteroaryl contains 5 to 6 ring atoms), aminoC₁₋₅alkyl, diaminoC₁₋₅alkyl, phthalimidoC₁₋₅alkyl, succinimidoC₁₋₅alkyl, SEM, C₁₋₅alkylcarbonyl, C₁₋₅alkylcarbonylC₁₋₅alkyl, C₁₋₅alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, arylC₁₋₅alkyloxycarbonyl and aryloxycarbonylC₁₋₅alkyl; A is a five to seven member heterocyclyl ring optionally substituted with one to two substituents independently selected from X; wherein the ring has an unsaturated bond of attachment at a ring carbon atom; has a ring nitrogen atom substituted with a substituent selected from W adjacent to the ring carbon of attachment; has a ring carbon atom adjacent to the ring carbon of attachment; optionally has 1 or 2 double bonds formed in the ring between adjacent ring members; and, optionally has 1 or 2 ring members independently selected from the group consisting of O, N and S; W is a substituent selected from the group consisting of hydrogen, C₁₋₅alkyl, C₁₋₅alkoxy, aminoC₁₋₅alkyl (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl), arylC₁₋₅alkyl and heteroarylC₁₋₅alkyl (wherein the aryl, heteroaryl and C₁₋₅alkyl portions of any of the foregoing substituents are optionally substituted with one to three substituents independently selected from the group consisting of halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl, heteroaryl, amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl) and nitrile); X is a substituent selected from the group consisting of C₁₋₅alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl, C₁₋₅alkoxy, amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl), aminoC₁₋₅alkyl (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl), aryl, arylC₁₋₅alkyl, heteroaryl and heteroarylC₁₋₅alkyl (wherein the aryl, heteroaryl and C₁₋₅alkyl portions of any of the foregoing substituents are optionally substituted with one to two substituents independently selected from the group consisting of halogen, C₁₋₅alkyl, C₁₋₅alkoxy, aryl, heteroaryl, amino (wherein amino is optionally substituted with one to two substituents independently selected from C₁₋₅alkyl) and nitrile); and pharmaceutically acceptable salts thereof; comprising, converting an intermediate compound of Formula II

wherein Y is a three to five member linear alkylene, alkenylene, heteroalkylene or heteroalkenylene chain optionally substituted with one to two substituents independently selected from X; wherein the alkenylene and heteroalkenylene chain has 1 or 2 double bonds formed in the chain between adjacent members; and, wherein the heteroalkylene and heteroalkenylene chain has 1 or 2 members independently selected from the group consisting of O, N and S; and, all other substituents are as previously defined; by ammonolysis, using an excess of a compound selected from H₂N(W) in an appropriate solvent, to form a secondary amine intermediate of Formula III; and,

coupling the amine at the 2 position of the triple bond by a Michael addition, in the presence of appropriate reagents and solvents, to form the compound of Formula I.
 22. The method of claim 21 wherein Y is a three to five member linear alkylene chain optionally substituted with one to two substituents independently selected from X.
 23. The method of claim 22 wherein Y is an unsubstituted three to five member linear alkylene chain.
 24. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
 25. A pharmaceutical composition comprising a compound according to claim 19 and a pharmaceutically acceptable carrier or diluent.
 26. A pharmaceutical composition comprising a compound according to claim 20 and a pharmaceutically acceptable carrier or diluent.
 27. A method for treating inflammatory diseases comprising administering a compound of claim 1 to a mammal suffering from an inflammatory disease at an effective dose.
 28. A method for treating inflammatory diseases comprising administering a pharmaceutical composition of claim 24 to a mammal suffering from an inflammatory disease at an effective dose.
 29. The method of claim 27 wherein the compound is administered orally and the effective dose is from about 0.1 mg/kg/day to about 100 mg/kg/day.
 30. The method of claim 29 wherein the effective dose is from about 0.1 mg/kg/day to about 50 mg/kg/day.
 31. The method of claim 27 wherein the inflammatory disease is arthritis.
 32. The method of claim 31 wherein the compound is administered orally and the effective dose is from about 0.1 mg/kg/day to about 100 mg/kg/day.
 33. The method of claim 32 wherein the effective dose is from about 0.1 mg/kg/day to about 50 mg/kg/day. 